Revised Abstract: The major goals of this Program Project Grant are to utilize two unique and complimentary hospital and population-based bladder cancer databases to further understand the etiology, diagnosis and prognosis of transitional cell carcinoma of the bladder. Project 1 will determine the role of de novo methylation of regulatory genes in the initiation and progression of human bladder cancer and will examine the effects of cigarette smoking and use of non-steroidal anti-inflammatory drugs (NSAIDs) use on the patterns of abnormal methylation. Project 2 will determine the role of COX-2 and DNA Methyltransferase expression in primary tumors and relate the expression levels to exposure levels of cigarette smoking and NSAID use. Project 3 will determine how the altered expression of cell-cycle regulatory genes plays a role in the genesis and prognosis of bladder cancer and will examine the expression of proteins encoded by genes studied in Projects 1 and 2, with the long-term goal of developing better techniques for predicting and for establishing better, more rational treatment. The Program Project will cover a wide range of aspects of bladder cancer, extending from cellular and molecular events during genesis of bladder cancer, through epidemiology, to clinically relevant translational issues such as chemoprevention, prediction of risk for recurrence and treatment response. The achievement of these goals will be assisted by three Core Facilities including an Administrative Core, a Biostatistics and Bladder Cancer Database Core and a Pathology Core. The goals of the Program Project Grant will be furthered by the close juxtapositioning of the research labs and the offices of the principal investigators involved in most of the experiments to be performed. The participating investigators have a considerable history of collaboration in the areas of translational research in the field of bladder cancer and these interactions will be formalized and enhanced by this Program Project Grant.